The transplanting of tissues such as organs is a well recognized technique in surgery. Unfortunately, a major, long-standing difficulty is the rejection of the transplanted tissue by the host. Briefly, the immune system of the host recognizes a foreign body (i.e., the transplanted tissue) and then rejects that foreign body. A variety of techniques exist for the suppression of rejection, and improved rates of success are now being achieved. A popular technique is to suppress the recipient's immune system, for example with cyclosporin. However, such immunosuppression techniques carry risks for the patient, and are therefore minimized, when possible, by attempting to determine prior to immunosuppression if the tissue exhibits characteristics of rejection.
A standard means of determining whether an organ is being rejected is the conduction of physical biopsies (such as an endomyocardial biopsy (EMB) for the heart). In the case of heart transplants, accurate diagnosis is vital for the effective care of the heart transplant, and percutaneous transvenous EMB is a standard method for such assessment of rejection. Crudely described, this means inserting a catheter comprising a device known as a bioptome, which comprises a wire with tiny jaws at the distal end, into a blood vessel. Many varieties of catheters and bioptomes are known in the art. See, e.g., U.S. Pat. No. 3,964,468; U.S. Pat. No. 4,953,559; U. S. Pat. No. 4,884,567; U.S. Pat. No. 5,287,857; U.S. Pat. No. 5,406,959; WO 96/35374; WO 96/35382; WO 96/29936; WO 96/35374. The distal end of the catheter is fed into an entry point, typically on the leg or neck, and then on to the heart chamber where a tiny piece of tissue is clamped in the jaws of the bioptome and removed for analysis.
This biopsy permits accurate detection of the presence and the severity of histologic changes in the transplanted tissue once the site of rejection is found. In particular, the heart material obtained from the biopsy is graded for the level or severity of the rejection. The International Society for Heart and Lung Transplantation (ISHLT), Kolbeck et al., Transplant Pathology, p. 200 (Am. Soc. Clin. Path., 1994), rates cardiac rejection as follows:
TABLE 2 International Society for Heart and Lung Transplantation Grade 0 No evidence of acute rejection Grade 1 Mild A. Focal/Perivascular B. Diffuse/Interstitial Grade 2 Moderate, Uni-focal Grade 3 Moderate, Multi-focal A. Several foci B. Diffuse Grade 4 Severe Ongoing Mild, moderate, severe Resolving
In an alternative formulation, Billingham's Histopathologic Classification of Rejection, Kolbeck et al., Transplant Pathology, p. 199 (Am. Soc. Clin. Path., 1994), establishes the features of tissue rejection as follows:
TABLE 3 Billingham's Histopathologic Classification of Acute Rejection in Human Heart Allograft Severity of Acute Prognostic and Rejection Features Implications Therapeutic Mild Rare (usually 1-2) localized Reversible, typically perivascular collections of without augmentation of mononuclear cells with limited immunosuppressive extension into the interstitium. therapy. No definite myocardial injury. Moderate Collection of "activated" Reversible, typically with perivascular and interstitial augmentation of therapy mononuclear cells with associated and rebiopsy. myocyte injury. Severe Widespread inflammatory Reversible, but with infiltrates including mononuclear difficulty. Requires cells and often polymorphonuclear augmentation of therapy. leukocytes and eosinophils. Multifocal tissue and small vessel necrosis is associated with fresh hemorrhage. Resolving Granulation tissue at various Reversed rejection, stages if collagenization. Includes spontaneously or numerous fibroblasts with therapeutically induced. scattered mononuclear cells, plasma cells and phagocytosed lipochrome pigment.
A patient may require an average of 5 and as many as 10 biopsies per biopsy procedure. Thus, over the first year of a heart transplant recipient, as many as 180 EMBs are taken. A typical schedule for EMBs is as follows:
TABLE 1 Right Ventricular Biopsy Protocol for Heart Transplant Period Time Frequency Procedures Immediate post- 0-4 weeks from day five, 6 operative twice weekly 4-6 weeks weekly 3 Late post-operative 2-3 months bimonthly 4 4-6 months monthly 3 6-12 months quarterly 2 Total First Year 18 After one year yearly (in the absence of rejection) After rejection 14-21 days therapy
EMBs, and other biopsies, are problematic, however, because during each biopsy a number of potential complications may occur. These complications include the following:
right ventricular perforation
cardiac tamponade
ventricular and supraventricular arrhythmia
embolus (thrombus or air)
pneumothorax air in the pleural cavity
infection
bleeding
EMBs are the principle method for monitoring cardiac allograft rejections.
Thus, the EMB, which is a physical biopsy and diagnostic aid, is hazardous for the patient. Attempts have been made to reduce the number of biopsies per patient, but these attempts have not been successful, due in part to the difficulty in pinpointing the sites where rejection starts and to the difficulty in assessing tissue without performing the actual biopsy.
Accordingly, there has gone unmet a need for methods and apparatus that reduce the number of EMBs that a patient must suffer subsequent to undergoing a transplant procedure. There has also gone unmet a need for methods and devices that assist in pinpointing sites where rejection starts. The present invention provides these and other related advantages.